Phosphonoacetic esters and acids as anti-inflammatories

ABSTRACT

Compounds useful in the treatment of inflammation structurally represented as Formula I ##STR1## one of X or Y is H and the other is selected from the group consisting of: ##STR2## or X and Y are taken together to form a ring selected from the group consisting of: ##STR3## as herein defined. The compounds are useful as anti-inflammatory and anti-arthritic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/US93/05365, filed Jun. 9,1993, which was a continuation of U.S. Ser. No. 07/926,879, filed Aug.7, 1992, abandoned.

BACKGROUND OF THE INVENTION

The present invention is directed toward phosphonoacetic esters, acids,and their pharmaceutically acceptable salts which are characterized by(Formula I) and which are useful as anti-inflammatories andanti-arthritic agents.

The present compounds are useful in humans and lower animals as a safeand effective treatment of diseases characterized by abnormal phosphateand calcium metabolism, and as a treatment of inflammation. Thesediseases include osteoporosis, Paget's disease, periodontal disease,rheumatoid arthritis, osteoarthritis, neuritis, bursitis, soft tissuemineral disorders, ankylosing spondylitis, atherosclerosis, multiplemyeloma of bone, metastatic bone disease, and mitral valvecalcification. They represent a novel method of treating inflammation.

DESCRIPTION OF THE RELATED ART

For state of the art purposes, U.S. Pat. No. 4,746,654 disclosesbisphosphonates useful as anti-inflammatory agents; Australian PatentA-51534/85 discloses bisphosphonates useful in treating abnormal calciumand phosphorous metabolism and useful in treating arthritis; and U.S.Pat. No. 3,683,080 discloses polyphosphonates, in particulardiphosphonates useful in inhibiting anomalous deposition andmobilization of calcium phosphate in animal tissue.

PCT/US92/05398 discloses pyrazolopyrimidines and pyrimidinylbisphosphonic esters useful as anti-inflammatories.

U.S. Pat. No. 5,071,840 discloses diphosphonic acids useful in treatingabnormal calcium and phosphate metabolism.

U.S. Pat. No. 3,962,433 discloses phosphono-dicarboxcylic acids usefulin treating calcium metabolism disorders.

SUMMARY OF THE INVENTION

In one aspect, the present invention is phosphonoacetic esters, acids,and its pharmaceutically acceptable salts which are structurallyrepresented by Formula I ##STR4## wherein R¹ is H, C₁ -C₆ alkyl, benzyl,phenyl, phenyl (substituted with 1 to 5 F, Cl, Br, I, NO₂, OCH₃ or C₁-C₄ alkyl);

R² is H, C₁ -C₆ alkyl, benzyl, phenyl, phenyl (substituted with 1 to 5F, Cl, Br, I, NO₂, OCH₃ or C₁ -C₄ alkyl), or where both R² 's are takentogether and form a CH₂ --CH₂, CH₂ --CH₂ --CH₂ or CH₂ --C(CH₃)₂ --CH₂ toform a heterocyclic ring containing the bonded P atom and two O atoms;

one of X or Y is H and the other is selected from: ##STR5## or X and Yare taken together to form a ring selected from: ##STR6##

In another aspect, the present invention comprises the use of thesecompounds in humans and lower animals as a safe and effective treatmentof chronic inflammatory diseases. These diseases include periodontaldisease, rheumatoid arthritis, osteoarthritis, pneumoconioses, Crohn'sdisease, chronic inflammatory bowel disease, chronic asthma,atherosclerosis, multiple sclerosis, and sarcoidosis.

In yet another aspect, the invention is a method for treatinginflammation by administering to an animal in need of such treatment ananti-inflammatory effective amount of a compound of Formula I. Routes ofadministration include oral, intramuscular, intravenous, transdermal,intra-articular, subcutaneous, or intraperitoneal. An effective amountis an amount whereby the symptoms of inflammation or arthritis such aspain and discomfort are relieved or reduced or mobility of the affectedarea is increased. A typical dosage is about 0.001 mg to 1.0 gram withdose determined by the particular mode of administration, use andfrequency of administration.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises phosphonoacetic esters, acids, and theirpharmaceutically acceptable salts which are characterized by (Formula I,above) and which are useful as anti-inflammatories and anti-arthriticagents. These compounds are particularly useful in the treatment ofarthritis and its associated symptoms such as inflammation and excessivebone growth or remodelling. In Formula I, the variable designations arefurther defined as follows.

The carbon content of various hydrocarbon containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i) -C_(j) defines thenumber of carbon atoms present from the integer "i" to the integer "j"inclusive. Thus, C₁ -C₃ alkyl refers to alkyl of 1-3 carbon atoms,inclusive, or methyl, ethyl, propyl, and isopropyl.

With respect to the above, C₁ -C₆ alkyl is methyl, ethyl, propyl, butyl,pentyl, hexyl, and isomeric forms thereof. The abbreviation "Ph" is usedin structures and formula to mean phenyl.

The term "halo" includes fluoro, chloro, bromo and iodo.

Pharmaceutically acceptable salts means salts useful for administeringthe compounds of this invention or useful forms the compounds may takein vitro or in vivo and include potassium, sodium, hydrochloride,hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate,lactate, mesylate, maleate, malonate, succinate, tartrate, citric acidand the like. These salts may be in hydrated form.

The phosphonoacetic esters, acids, and derivatives (Formula I) useful asanti-inflammatories and antiarthritics are prepared as shown in Examples1-16. Phosphonoacetates are well documented in the chemical literatureand serve as useful starting materials for the Horner-Wadsworth-Emmonsreaction (a modification of the Wittig reaction) in the synthesis ofalkenes. See generally, A. W. Johnson in "Ylid Chemistry," AcademicPress, p. 205-212 (1966); and B. M. Trost (ed.), "Comprehensive OrganicSynthesis," Pergammon Press, Vol. 1, p. 761-71 (1991).

Briefly, the linear compounds are prepared via a Michael type additionreaction at -78° C. of an active methylene compound to aphosphonoacrylate. The pyrazolines are prepared via a dipolarcycloaddition of the appropriate diazo derivative to aphosphonoacrylate. The cyclopropane(s) is formed as a side product inthis reaction.

The aziridine(s) is formed via nitrene addition to a phosphonoacrylate.

The corresponding phosphonic acids may be prepared by treating the esterwith trimethylsilyl bromide followed by an aqueous workup.

The Formula I compounds of this invention have been tested in a DelayedType Hypersensitivity Granuloma Assay (DTH GRA) model for inflammation.This assay is described by Dunn, C. J. et al., "Development of adelayed-type hypersensitivity granuloma model in the mouse for the studyof chronic immune-mediated inflammatory disease," Agents and Actions,27, 3/4 (1989) and "Murine Delayed-Type Hypersensitivity Granuloma,"Int. J. Immunopharmc., 12, 8, 899-904 (1990).

Briefly, mBSA-sensitized mice have a DTH granuloma (DTH GRA) lesioninduced by subcutaneously implanting a mBSA-soaked filter which isexcised after nine days. Compounds are administered to the mice todetermine their effect on the lesions. The results are recorded aspercent inhibition. The larger the inhibition, the more effective thecompound. Inhibition of 10 to 20% is considered to indicateanti-granuloma activity. Greater than 30% inhibition is good activity.

The DTH GRA data obtained from the compounds of Formula 1 are shown inTable 2. The compounds are scored as having anti-inflammatory activityat 10-20% inhibition and good activity at greater than 30% inhibition.

The "compound designations" correspond to the Examples' designations.The particular compounds designated are as follows

                  TABLE 1                                                         ______________________________________                                        COMPOUND #    R.sup.1 R.sup.2    X   Y                                        ______________________________________                                        1             C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                          a.  H                                        2             CH.sub.3                                                                              CH.sub.3   b.  H                                        3             C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                          c.  H                                        4             CH.sub.3                                                                              CH.sub.3   d.  H                                        5             CH.sub.3                                                                              CH.sub.3   e.  H                                        6             CH.sub.3                                                                              CH.sub.3   f.  H                                        7             CH.sub.3                                                                              CH.sub.3   g.  H                                        8             CH.sub.3                                                                              CH.sub.3   i.  --                                       9             CH.sub.3                                                                              CH.sub.3   ii. --                                       10            CH.sub.3                                                                              CH.sub.3   iii.                                                                              --                                       11            CH.sub.3                                                                              CH.sub.3   iv. --                                       12            H       CH.sub.3   f.  H                                        13            H       H          f.  H                                        14            t-butyl CH.sub.3   b.  H                                        15            t-butyl CH.sub.3   f.  H                                        16            H       CH.sub.3   f.  H                                        ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Compound #      % Inhibition (10 MPK, PO)                                     ______________________________________                                         1              37        (at 50 MPK)                                          2              26                                                             3              21                                                             4              37                                                             5              32                                                            6a              51                                                            6b              37                                                             7              38                                                             8              59                                                             9              37                                                            10              47                                                            11              42                                                            15              21                                                            ______________________________________                                    

EXAMPLE 1

Benzenepentanoic acid, α-(diethoxyphosphinyl)-δ-oxo-, ethyl esterAcetophenone (0.51 ml, 4.4 mmol) dissolved in THF (15 ml) was cooled to-78° C. and treated with LiHMDS (4.8 ml, 4.8 mmol). After stirring for30 minutes, a solution of triethyl-2-phosphonoacrylate (0.94 g, 4.0mmol) in THF (5 ml) was added. The mixture was stirred at -78° C. for 30minutes then warmed to 0° C. for 15 minutes. Quenched with sat. NH₄ Cland removed the solvents in vacuo. Dissolved the residues in ethylacetate and washed 2×1N HCl, H₂ O, 3× sat. NaHCO₃, sat. NaCl then driedover MgSO₄. Filtered, removed the solvent in vacuo and chromatographedthe crude oil on SiO₂ (50 g) with 1:1 ethyl acetate/hexane. Recovered0.85 g of a light oil (2.4 mmol, 60%) of benzenepentanoic acid,α-(diethoxyphosphinyl)-δ-oxo-, ethyl ester.

Mass Spec: m/e 356 (M⁺), 328, 311, 237, 224, 105, 77

Infra Red: vmax (cm⁻¹) 1733, 1685, 1598, 1581, 1449, 1391, 1368, 1252

NMR: δ (CDCl₃) 7.94 (d, 2H), 7.57 (m, 1H), 7.46 (t, 2H), 4.26-4.13 (m,8H), 3.21-3.00 (m, 3H), diastereotopic (2.42-2.31 (dt, 2H)), 1.37-1.26(m, 12H).

EXAMPLE 2

Benzenepentanoic acid, α-(dimethoxyphosphinyl)-3-fluoro-δ-oxo-, methylester

Reaction of trimethylphosphonoacrylate with 3-fluoroacetophenone wascarried out as follows. 3-Fluoroacetophenone (0.75 g, 5.43 mmol) wasdissolved in tetrahydrofuran (10 mL), placed under nitrogen and cooledto -78° C. A solution of 1M lithium hexamethyldisilazide in THF (5.70mL, 5.70 mmol) was added over 10-15 sec via syringe and septum. Afterstirring for 45 min, trimethylphosphonoacrylate (1.0 g, 5.15 mmol) wasadded over 30 sec. The reaction was allowed to come to ambienttemperature and stirred overnight. Saturated ammonium chloride solution(10 ml) was added and most of the THF removed on a rotary evaporator.The residue was partitioned between methylene chloride (100 ml) and 1NHCl (20 ml). The organic layer was washed with water (20 ml), 5% sodiumbicarbonate solution (20 ml) and brine (50 ml). The yellow solution wasdried over MgSO₄, filtered and evaporated to yield an amber gum (1.4 g).Chromatography of the gum over silica gel (150 g, 40-60 μm)made up in75% ethyl acetate-hexane eluted unreacted 3-fluoroacetophenone. Gradientelution with 100% ethyl acetate and then 1% methanol-ethyl acetateeluted the product over ca. 700 ml. Evaporation gave thephosphonoacetate benzenepentanoic acid,α-(dimethoxyphosphinyl)-3'-fluoro-δ-oxo-, methyl ester as a pale yellowviscous oil (730 mg, 43%).

Mass Spec: m/e 332 (2), 304 (9), 301 (12), 195 (23), 182 (66), 163 (12),151 (15), 124 (18), 123 (100), 109 (11), 95 (25)

Infra Red: vmax 2957, 1737, 1690, 1589, 1445, 1255, 1152, 1054, 1032,830, 783 cm⁻¹

NMR: δ (CDCl₃); 2.29-2.45 (m, 2H, CH₂); 2.97-3.30 (m, 3H, CH plus CH₂CO); 3.72-3.90 (m, 9H, 3×CH₃ O); 7.27 (m, 1H, aromatic H₅); 7.45 (m, 1H,aromatic H₄); 7.63 (m, 1H, aromatic H₆); 7.74 (m, 1H, aromatic H₂).

EXAMPLE 3

Benzenepentanoic acid, α-(diethoxyphosphinyl)-δ-oxo-γ-phenyl-, ethylester

Deoxybenzoin (0.86 g, 4.4 mmol) dissolved in THF (15 ml) and cooled to-78° C. was treated with LiHMDS (4.8 ml, 4.9 mmol) then stirred for 30minutes. A solution of triethyl-2-phosphonoacrylate (0.94 g, 4.0 mmol)in THF (5 ml) was added. After stirring for 30 minutes, the reactionmixture was warmed to 0° C. for 30 minutes. Quenched with sat. NH₄ Cland removed solvents in vacuo. Dissolved the residue in ethyl acetateand washed 2×1N HCl, H₂ O, 3× sat. NaHCO₃, sat. NaCl then dried overMgSO₄. Filtered, removed solvents in vacuo and chromatographed on SiO₂(50 g) with 2:3 ethyl acetate/hexane. Recovered 1.24 g of a light oil,(2.8 mmol, 72%) of benzenepentanoic acid,α-(diethoxyphosphinyl)-δ-oxo-γ-phenyl-, ethyl ester.

Mass Spec: m/e 432 (M⁺), 387, 328, 327, 224, 105, 77

Infra Red: vmax (cm⁻¹) 1732, 1681, 1598, 1580, 1492, 1447, 1391, 1368,1254, 1153

NMR: δ (CDCl₃) 7.93 (t, J=7.2, 2H), 7.49-7.45 (m, 1H), 7.40-7.20 (m,7H), diastereotopic (4.74 (t, J=9.1), 4.72 (t, J=9.1), 1H), 4.29-3.97(m, 6H), diastereotopic (3.09 (ddd, J_(d1) =4.7, J_(d2) =10.2, J_(d3)=23), 2.86 (ddd, J_(d1) =4.8, J_(d2) =10, J_(d3) =23), 1H), 2.79-2.60(m, 1H), 2.53-2.35 (m, 1H), 1.37-1.12 (m, 9H).

EXAMPLE 4

3-Pyridinepentanoic acid, α-(dimethoxyphosphinyl)-δ-oxo-, methyl ester

The reaction of trimethylphosphonoacrylate and 3-acetylpyridine wascarried out as follows. 3-Acetylpyridine (0.63 g, 5.21 mmol) wasdissolved in THF (10 ml), placed under nitrogen and cooled to -78° C. A1M solution of lithium hexamethyldisilazide in THF (5.50 ml, 5.50 mmol)was added via syringe and septum, and the cooled mixture stirred for 35min. A solution of trimethylphosphonoacrylate (1.0 g, 5.15 mmol) in THF(3 ml) was added over 1 min. The mixture was allowed to come to ambienttemperature over 3 hr when a saturated solution of ammonium chloride (10ml) was added. Most of the THF was removed on a rotary evaporator andthe residue treated with ethyl acetate (100 ml) and water (20 ml). Theorganic layer was washed with brine (30 ml) and dried (Na₂ SO₄).Filtration and evaporation yielded an amber oil (1.2 g), which waschromatographed over silica gel (150 g, 40-60 μm). Gradient elution from100% ethyl acetate to 4% methanol-ethyl acetate afforded the product3-pyridinepentanoic acid, α-(dimethoxyphosphinyl)-δ-oxo-, methyl esterin the later fractions as a pale yellow oil (670 mg, 41%).

EXAMPLE 5

Ferrocene, (4-(dimethoxyphosphinyl)-5-methoxy-1,5-dioxopentyl)

The reaction of trimethylphosphonoacrylate and acetylferrocene wascarried out as follows. Acetylferrocene (1.17 g, 5.13 mmol) was stirredin THF (10 ml) under nitrogen and cooled to -78° C. A 1M solution oflithium hexamethyldisilazide (5.15 ml, 5.15 mmol) in THF was added over1 min and the reaction stirred for 30 min. A solution oftrimethylphosphonoacrylate (1.0 g, 5.15 mmol) in THF (3 ml) was addedand the reaction allowed to equilibrate with room temperature overnight.Saturated ammonium chloride solution (10 ml) was added and the THFremoved on a rotary evaporator. Ethyl acetate (100 ml) was added andwashed with water (50 ml), and brine (50 ml). After drying (Na₂ SO₄),filtration and evaporation, a blood red oil (1.9 g) was obtained.Chromatography over silica (1.50 g, 40-60 μm) eluting with 1%methanol-chloroform afforded the ferrocenylphosphonoacetate ferrocene,(4-(dimethoxyphosphinyl)-5-methoxy-1,5-dioxopentyl)- as a deep redviscous oil (900 mg, 42%).

Mass Spec: m/e 423 (12), 422 (51), 358 (17), 357 (100), 267 (15), 237(17), 219 (6), 207 (10), 189 (7), 121 (12).

Infra Red: ν_(max) 2955, 1736, 1666, 1455, 1257, 1053, 1029, 827 cm⁻¹.

NMR: δ (CDCl₃): 2.24-2.40 (m, 2H, CH₂); 2.72-2.98 (m, 2H, CH₂ CO);3.17-3.34 (m, 1H, CH); 3.80 (s, 3H, CO₂ CH₃); 3.84 (d, J=11.0 Hz, 6H,2×CH₃ OP); 4.20 (s, 5H, C₅ H₅); 4.45-4.54 (m, 2H, cyclopentadienyl);4.73-4.82 (m, 2H, cyclopentadienyl).

EXAMPLE 6

(Part A):

2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl-, methylester

The reaction of trimethylphosphonoacrylate and2,3-dimethyl-6-phenylpyrimidinone was carried out as follows.2,3-Dimethyl-6-phenylpyrimidinone (1.03 g, 5.15 mmol) was stirred undernitrogen in THF (10 ml) then cooled to -78° C. A 1M solution of lithiumhexamethyldisilazide (5.50 ml, 5.50 mmol) in THF was added via a syringeand septum. After stirring at -178° C. for 40 min,trimethylphosphonoacrylate (1.0 g, 5.15 mmol) in THF (3 ml) was added tothe orange solution. The reaction was allowed to come to ambienttemperature whilst stirring overnight. A saturated solution of ammoniumchloride (10 ml) was added and most of the THF removed on the rotaryevaporator. Ethyl acetate (100 ml) and water (20 ml) were added to theresidue. The organic layer was washed with 1N.HCl (25 ml), brine (25ml), dried (Na₂ SO₄), filtered and evaporated to afford a sticky solid(1.74 g). The solid was washed from the flask with a littlemethyl-t-butyl ether to yield a cream solid (1.33 g, 65%).Recrystallization from acetone-hexane gave the phosphonoacetate2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl-, methylester as translucent pale yellow crystals (1.05 g) mp 114°-5°.

EXAMPLE 6

(Part B):

2-Pyrimidinebutanoic acid, α-(dimethoxyphosphonicacid)-1,6-dihydro-1-methyl-6-oxo-4-phenyl-, methyl ester

The hydrolysis of 2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl-, methylester yielded its acid derivative. The phosphonoacetate (300 mg, 0.76mmol) was stirred in chloroform (15 ml) and trimethylsilylbromide (1.0ml, 1.16 g, 7.58 mmol) added. The mixture was heated under reflux for 18hours, cooled and the solvent removed to afford a glassy gum. Ethylacetate (25 ml) and water (10 ml) were added to give an opaque mixture.Filtration of the mixture gave a gummy solid which was washed with water(10 ml). The gummy solid was dried in vacuo overnight to afford a whitecrusty solid mp 225°-7° as the phosphonic acid (260 mg, 93%).

EXAMPLE 7

Pyrazolo(1,5-a)pyrimidine-7-butanoic acid,3-cyano-α-(dimethoxyphosphinyl)-2,5-dimethyl-, methyl ester

The reaction of trimethylphosphonoacrylate and a pyrazolopyrimidine wascarried out as follows.2,5,7-Trimethylpyrazolo(1,5-a)pyrimidine-3-carbononitrile (0.96 g, 5.15mmol) was stirred in pyridine (10 ml) under nitrogen and cooled in anice-ethanol bath. A solution of 1M lithium hexamethyldisilazide (5.50ml, 5.50 mmol) in THF was added to afford a deep red solution. Afterstirring for 20 min, a solution of trimethylphosphonoacrylate (1.0 g,5.15 mmol) in THF (3 ml) was added and the mixture allowed to warm toambient temperature over 2 hr. A saturated solution of ammonium chloride(10 ml) was added and most of the solvent removed on a rotaryevaporator.

The residue was azeotroped with toluene (100 ml) and treated with ethylacetate (100 ml) and water (50 ml). The organic layer was washed withbrine (30 ml), dried (Na₂ SO₄), filtered and evaporated to give a gum(1.57 g) which crystallized upon addition of methyl-t-butyl ether. Theresultant solid Pyrazolo(1,5-a)pyrimidine-7-butanoic acid,3-cyano-α-(dimethoxyphosphinyl)-2,5-dimethyl-, methyl ester (1.21 g,62%) was recrystallized from acetone-hexane as cream crystals mp164°-5°.

EXAMPLE 8

1H-Pyrazole-5-carboxylic-acid,3-carboethoxy-5-(dimethoxyphosphinyl)-4,5-dihydro, methyl ester

The reaction of trimethylphosphonoacrylate and ethyldiazoacetate wascarded out as follows. Trimethylphosphonoacrylate (1.0 g, 5.15 mmol) wasdissolved in methyl-t-butyl ether followed by ethyl diazoacetate (0.60g, 5.26 mmol). After stirring overnight, the reaction was filtered andthe resultant solid (880 mg, 55%) recrystallized from acetone-hexane toafford off-white granules of the pyrazoline1H-Pyrazole-5-carboxylic-acid,3-carboethoxy-5-(dimethoxyphosphinyl)-4,5-dihydro, methyl ester (699 mg)mp 100°-102°.

EXAMPLE 9

1H-Pyrazole-5-carboxylic acid,3-benzoyl-5-(dimethoxyphosphinyl)-4,5-dihydro-, methyl ester

The reaction of trimethylphosphonoacrylate and diazoacetophenone wascarried out as follows. Diazoacetophenone (0.75 g, 5.14 mmol) wasdissolved in methyl t-butyl ether (20 ml) followed bytrimethylphosphonoacrylate (1.0 g, 5.15 mmol). After stirring at ambienttemperature for 5 hr, the resultant precipitate was filtered (180 mg)and identified as the pyrazoline. Evaporation of the filtrate gave ayellow viscous oil which was placed in a refrigerator over the weekend.Attempts to dissolve this oil in a little 50% hexane-ether afforded moresolid (230 mg) which was filtered and combined with the first crop(combined: 410 mg, 23%). Recrystallization from acetone-hexane gave thepyrazoline 1H-pyrazole-5-carboxylic acid,3-benzoyl-5-(dimethoxyphosphinyl)-4,5-dihydro-, methyl ester as whitecrystals (338 mg) mp 152°.

EXAMPLE 10

Cyclopropanecarboxylic acid, 2-benzoyl-1-(dimethoxyphosphinyl)-, methylester

The reaction mixture filtrate from Example 9 was chromatographed (SiO₂,40-60 μm, 150 g) with a gradient of 25-50% acetone-hexane. Thecyclopropane (60 mg, 4%) Cyclopropanecarboxylic acid,2-benzoyl-1-(dimethoxyphosphinyl)-, methyl ester was eluted in thelatter fractions as a colorless gum which slowly crystallized as a whitesolid mp 62°-4°.

EXAMPLE 11

2-Aziridinecarboxylic acid,1-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-(dimethoxyphosphinyl)-,methyl ester

The oxidation of N-aminophthalimide in the presence oftrimethylphosphonoacrylate was carried out as follows.N-Aminophthalimide (1.0 g, 6.17 mmol) and trimethylphosphonoacrylate(2.5 g, 12.9 mmol) were stirred in methylene chloride (25 ml) and leadtetraacetate (95%) (2.75 g, 5.89 mmol) added over 3 min. After stirringfor 1 hr, the reaction was filtered and evaporated. The resultant gumwas chromatographed (SiO₂, 500 g, 40-60 μm) eluting with a gradient of1-4% methanol-chloroform. The aziridine was eluted in the laterfractions as a yellow gum (2.84 g). A small amount of hexane was addedand the gum placed in the freezer for 2 days. After removal from thefreezer, crystals began to form. Filtration afforded a sticky solidwhich was recrystallized from acetone-hexane to yield the aziridine (780mg, 36%). A second recrystallization gave white crystals2-Aziridinecarboxylic acid,1-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-(dimethoxyphosphinyl)-,methyl ester (680 mg, 31%) mp 123°-4°.

EXAMPLE 12

2-Pyrimidinebutanoic acid,α-(methoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl

2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl-, methylester (0.969 g, 2.46 mmol) was heated to reflux in 2N KOH (5 ml) for 20hours. After cooling, it was diluted with water to dissolve solids andthen eluted through a bed of Bio-Rad AG 50W-X4 resin (H⁺ form, 10 cm×2.5cm² column, 200-400 mesh) with water. The sample was concentrated invacuo: 0.84 g (2.3 mmol, 93%).

NMR: δ (CD₃ OD) 8.08 (m, 2H), 7.47 (m, 3H), 6.83 (s, 1H), 3.77 (d, J=11,3H), 3.57 (s, 3H), 3.33 (m, 1H), 3.04 (m, 2H), 2.51 (m, 2H)

EXAMPLE 13

2-Pyrimidinebutanoic acid,α-phosphon-1,6-dihydro-1-methyl-6-oxo-4-phenyl-

2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl (0.403 g,1.1 mmol) (from Example 12, above) was slurried in bromotrimethylsilane(4 ml, 30 mmol) and heated to reflux for 16 hours. Solvent was removedand the sample was dissolved in water. After stirring for 1 hour, it waspartitioned between ethyl acetate and water, the aqueous layer wascollected and lyophilized. The crude product was redissolved in water,and the resulting solid collected: 150 mg (0.4 mmol, 39%) mp 185°-187°C.

EXAMPLE 14

Benzenepentanoic acid, α-(dimethoxyphosphinyl)δ-oxo, dimethyl ethylester

t-Butyl-dimethoxyphosphonoacetate (25.74 g, 0.115 mol) was dissolved inmethanol (380 ml) then treated with paraformaldehyde (20.0 g, 0.670 mol)and diethylamine (14.0 ml, 0.134 mol). The reaction mixture was stirredat 22° C. for 60 hours then concentrated in vacuo. Ethyl acetate wasadded and washed 3×1N HCl, H₂ O, 3× sat. NaHCO₃, sat. NaCl, and driedwith MgSO₄. The crude methyl ether was concentrated in vacuo to recover41.6 g of colorless oil. Phosphoric acid (85%, 1.1 ml) was added and theproduct distilled, t-butyl-2-(dimethoxyphosphinyl)-acrylate: 17.7 g (75mmol, 65%) bp₀.2 110°-115° C.

3'-Fluoroacetophenone (1.85 ml, 15.1 mmol) dissolved in THF (25 ml) andcooled to -78° C. was treated with LiHMDS (15.4 ml, 15.4 mmol) andstirred for 30 minutes. A solution oft-butyl-2-(dimethoxyphosphinyl)-acrylate (3.56 g, 15.1 mmol) in THF (5ml) was added, stirred for 10 minutes, then warmed to 0° C. for 2 hours.The reaction was quenched with sat. NH₄ Cl, dissolved in ethyl acetate,washed 3×1N HCl, H₂ O, 3× sat. NaHCO₃, sat. NaCl, dried with MgSO₄, thenstripped. The sample was purified by chromatography (SiO₂, hexane/ethylacetate): 635 mg (1.7 mmol, 63%)

NMR: δ (CDCl₃) 7.74 (d, J=7.7, 1H), 7.63 (m, 1H), 7.45 (m, 1H), 7.27 (m,1H), 3.82 (d, J=11, 3H), 3.81 (d, J=11, 3H), 3.20-3.00 (m, 3H), 2.32 (m,2H), 1.48 (s, 9H)

EXAMPLE 15

2-Pyrimidine butanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl,dimethylethyl ester

2,3-Dimethyl-6-phenyl-pyrimidin-4(3H)-one (1.017 g, 5.08 mmol),dissolved in dry THF (10 ml) and cooled to -78° C., was treated withLiHMDS (5.3 ml, 5.3 mmol) and stirred for 30 minutes. A solution oft-butyl-2-(dimethoxyphosphinyl)-acrylate (1.14 g, 4.82 mmol) in THF (5ml) was added, stirred for 10 minutes, then warmed to 0° C. for 30minutes. The reaction was quenched with sat. NH₄ Cl, dissolved in ethylacetate, washed 3×1N HCl, H₂ O, 3× sat. NaHCO₃, sat. NaCl, dried withMgSO₄, then stripped. The sample was purified by chromatography (SiO₂,10% MeOH/ethyl acetate): 1.31 g. The sample solidified upon standing andwas recrystallized from methyl t-butyl ether: 0.90 g (2.0 mmol, 43%) mp94.5°-96° C.

EXAMPLE 16

2-Pyrimidinebutanoic acid, α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl

2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl,dimethylethyl ester (3.007 g, 6.89 mmol) (from Example 16, above) washeated to reflux in formic acid (55 ml) for 2 hours, then cooled and theexcess solvent removed. The solid was treated with water, stirred for 1hour, then the precipitate was filtered and dried under vacuum: 2.4 g(6.3 mmol, 91%) mp 150° C.

What is claimed:
 1. A compound of Formula I or pharmaceuticallyacceptable salts thereof wherein Formula I is ##STR7## wherein R¹ is H,C₁ -C₆ alkyl, benzyl, phenyl, phenyl substituted with 1 to 5 F, Cl, Br,I, NO₂, OCH₃ or C₁ -C₄ alkyl;R² is H, C₁ -C₆ alkyl, benzyl, phenyl,phenyl substituted with 1 to 5 F, Cl, Br, I, NO₂, OCH₃ or C₁ -C₄ alkyl,or where both R² 's are taken together to form a CH₂ --CH₂, CH₂ --CH₂--CH₂ or CH₂ --C(CH₃)₂ --CH₂ to form a heterocyclic ring containing thebonded P atom and the two O atoms; Y is hydrogen; and X is ##STR8## 2.The compound of claim 1 which isa. 3-Pyridinepentanoic acid,α-(dimethoxyphosphinyl)-δ-oxo-, methyl ester; b. 2-Pyrimidinebutanoicacid, α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl-,methyl ester; c. 2-Pyrimidinebutanoic acid, α-(dimethoxyphosphonicacid)-1,6-dihydro-1-methyl-6-oxo-4-phenyl-, methyl ester; d.Pyrazolo(1,5-a)pyrimidine-7-butanoic acid,3-cyano-α-(dimethoxyphosphinyl)-2,5-dimethyl-, methyl ester; e.2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl; f.2-Pyrimidinebutanoic acid,1,6-dihydro-1-methyl-6-oxo-4-phenyl-α-phosphono; g. 2-Pyrimidinebutanoic acid,α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl,dimethylethyl ester; and h. 2-Pyrimidinebutanoic acid, α-(dimethoxyphosphinyl)-1,6-dihydro-1-methyl-6-oxo-4-phenyl.
 3. A method fortreating inflammation comprising administering an anti-inflammatoryeffective amount of a compound of Formula I according to claim 1 to ananimal, including humans, in need thereof.
 4. The method of claim 3wherein said compound is administered to a patient in need thereof in ananti-inflammatory effective amount of from 0.001 mg to 1.0 gram and isadministered orally, intramuscularly, intravenously, transdermally,intra-articularly, subcutaneously, or intraperitoneally.